Work in this laboratory has been focused on the determination of three- dimensional structures of larger proteins in solution by NMR, with a particular emphasis on protein-protein, protein-ligand and protein-DNA complexes. A considerable effort has been placed on the development of three- and four-dimensional heteronuclear NMR to extend the application of NMR as a method for determining three-dimensional structures of proteins in solution beyond the limits of conventional two-dimensional NMR (approximately 100 residues) to molecules in the 150 to 400-residue range. High resolution solution structures of a number of proteins have been determined. These include the oligomerization domain of p53, a complex of human thioredoxin with its target site from the transcription factor NFkB, the DNA binding domain of Mu transposase, the DNA binding domain of HIV-1 integrase, and the specific complex of human SRY (the male sex determining factor) with DNA. The latter provides the molecular basis for understanding mutations in SRY that lead to 46X,Y sex reversal. Studies on protein hydration have revealed the presence of conformationally disordered water within a large 100-200_3 internal hydrophobic cavity of interleukin-1b. In addition, methodological advances have been made with regard to refinement of NMR structures, including the use of coupling constants, carbon chemical shifts and proton chemical shifts directly into the target functions employed in refinement.